IL-6 is a cytokine which is also called B cell stimulating factor 2 (BSF2) or interleukin β2. IL-6 was discovered as a differentiation factor involved in the activation of B-lymphatic cells (Hirano, T. et al., Nature (1986) 324, 73-76). Thereafter, it was found to be a multifunctional cytokine that influences various functions of cells (Akira, S. et al., Adv. in Immunology (1993) 54, 1-78). IL-6 has been reported to induce the maturation of T-lymphatic cells (Lotz, M. et al., J. Exp. Immunol. (1988) 167, 1253-1258).
IL-6 transmits its biological activity through two types of proteins on the cell. One is IL-6 receptor, a ligand-biding protein with a molecular weight of about 80 kD, to which IL-6 binds (Taga, T. et al., J. Exp. Med. (1987) 166, 967-981; Yamasaki, K. et al., Science (1987) 241, 825-828). IL-6 receptor occurs not only in the membrane-bound form that penetrates through and is expressed on the cell membrane but also as a soluble IL-6 receptor consisting mainly of the extracellular region.
The other is a membrane-bound protein gp130 having a molecular weight of about 130 kD that is involved in non-ligand-binding signal transduction. IL-6 and IL-6 receptor form the IL-6/IL-6 receptor complex, which, after binding to gp130, transmits its biological activity to the cell (Taga, T. et al., Cell (1989) 58, 573-581).
An IL-6 antagonist is a substance that inhibits the transduction of biological activity of IL-6. As the IL-6 antagonist, there have been known so far antibody directed against IL-6 (anti-IL-6 antibody), antibody directed against IL-6 receptor (anti-IL-6 receptor antibody), and antibody directed against gp130 (anti-gp130 antibody), altered IL-6, partial peptides of IL-6 or IL-6 receptor and the like.
Anti-IL-6 receptor antibody has been described in several reports (Novick D. et al., Hybridoma (1991) 10, 137-146, Huang, Y. W. et al., Hybridoma (1993) 12, 621-630, International Patent Publication WO 95-09873, French Patent Application FR 2694767, U.S. Pat. No. 521,628). Humanized PM-1 antibody has been known that was obtained by grafting the complementarity determining region (CDR) of one of them, a mouse antibody PM-1 (Hirata, Y. et al., J. Immunology (1989) 143, 2900-2906), to a human antibody (the International Patent Publication WO 92-19759).
Pancreatitis is an inflammatory disease in which the activation of pancreatic enzymes causes autolysis in pancreatic tissues. There have been reported that the amount of IL-6 produced in the peripheral blood mononuclear cells is significantly high in patients with pancreatitis as compared to healthy normal humans, and that IL-6 production from the peripheral blood mononuclear cells is high in cases of acute pancreatitis with systemic complications as compared to those with no complications (de Beaux A. C. et al., Brit. J. Surgery, 83, 1071-5, 1996). Furthermore, since blood levels of IL-6 are higher and respond earlier than other parameters in severe cases of acute pancreatitis, they have been considered to be a prognostic indicator for severity of pancreatitis (Inagaki, T. et al., Pancreas, 14, 1-8, 1997).
It has been suggested that IL-1 and TNF closely correlate with the disease states, and mice lacking receptors to both of the cytokines do not suffer serious disease conditions, and show markedly decreased mortality rate (Denham, W. et al., Gastroenterology, 113, 1741-6, 1997). Attempts have been made to treat pancreatitis using these inhibitors in animal models (Norman, J. et al., Surgery, 117, 648-6755, 1995, Hughes, C. B. et al., American J. Surgery, 171, 274-280, 1996, Norman, J. et al., surgery, 120, 515-621, 1996).
However, no attempts have been made to specifically suppress the biological activity of IL-6 using IL-6 antagonists such as anti-IL-6 receptor antibody in pancreatitis, and it was unknown that IL-6 antagonists such as anti-IL-6 receptor antibody exhibit therapeutic effects on pancreatitis.